cell activation is dependent on TCR recognition and cooperating signaling systems that provide positive or negative responses governing the quality of a T cell response. Cosignaling systems are emerging as important targets to enhance the immune response to tumor or pathogens and attenuate autoimmune diseases, yet these systems remain inadequately defined. Two major functional groups of cosignaling regulators are recognized: receptors with an Ig-like fold and members of the TNF receptor superfamily. We identified a novel inhibitory cosignaling pathway between HVEM (herpesvirus entry mediator;TNFRSF14) and BTLA (B-T lymphocyte attenuator), connecting the TNFR and Ig cosignaling families. The HVEM-BTLA interaction functions as an inhibitory pathway for T cell activation through an ITIM motif of BTLA. By contrast, the LIGHT-HVEM pathway provides positive cosignaling system in T cell activation particularly in mucosal inflammation, but the functional consequences of LIGHT-HVEM-BTLA signaling are unknown. We propose the LIGHT-HVEM-BTLA interaction provides a critical control mechanism for the regulation T cell activation, which is the overall focus of this application. A variety of reagents have been developed for this project including specific agonists and antagonists, e.g., decoy receptors, specific agonist antibodies and ligands for use with human systems, and mice genetically deficient in HVEM, LIGHT, and BTLA. Two aims are proposed to address the role of LIGHT-HVEM-BTLA system in T cell activation. The first aim addresses the structural features that allow HVEM to serve as a molecular switch between positive and inhibitory cosignaling. Structural and cell-cell interaction models utilizing a human culture system will be used to define the directionality of HVEM-BTLA interaction and how LIGHT controls the activation of BTLA and HVEM. Aim 2 is directed at defining LIGHT-HVEM-BTLA system using in vivo models of lung inflammation that are controlled by both CD4 and CDS T cells, involving Type 1 or Type 2 cytokines by assessing responses in HVEM-, BTLA-, or LIGHT-deficient mice and OT-II and OT-I TCR transgenic HVEM-deficient mice. Collectively, this project will provide a comprehensive perspective on the role of LIGHT-HVEM-BTLA cosignaling system in a lung inflammation model providing the foundation for exploiting this system as a therapeutic intervention. Lay audience: We discovered several proteins that form a communication network between white bloods cells, which control inflammation. Altering this communication system may help stop unwanted inflammation that occurs in autoimmune diseases, or to enhance immunity to viruses or cancer.